Principal Investigator/Program Director (Last, First, Middle): August, Avery Asthma affects millions of people worldwide and is gaining prevalence in the U.S. with the greatest increase seen among inner city African Americans and Hispanics. The reasons for this increase are not well understood, but may be the result of a complex interplay of genetic, socio-economic, behavioral, and environmental factors. Patients with allergic asthma manifest airway inflammation, and some show hallmarks of a classic Th2 response and Airway Hyperresponsiveness. This Th2 type response points to a prominent role for these cells and their cytokines in the pathology of this disease. An understanding of the development of these cells will allow us to develop approaches to prevent or decrease the severity of this disease. Our long-range goal is to provide a detailed understanding of Th2 cell development, and the effect of Th2 cells and their cytokines on allergic asthma. In pursuit of that goal, the objective of this renewal application is to continue to determine the role of Itk in T cell subset differentiation and cytokine production in the development of allergic asthma. The central hypothesis is that Itk regulates the development of specific T cell subsets, contributing to the development of allergic asthma. Our rationale is a better understanding of Th2 cell development and cytokine production will provide us with information needed to rationally design methods to treat diseases such as allergies and asthma. We will test our hypothesis by pursuing the following three specific aims: 1) Determine the role of Itk in the development of T cell subsets;2) Determine the role of Itk in chemokine receptor function;and 3) Determine the role of Tec kinase signals in regulating allergic airway inflammation. The proposed work is innovative, and we are well poised to conduct these studies because we will be taking advantage of mouse genetic systems lacking various Tec kinases or mutant forms of these kinases. This information will have a significant impact on human health, as we expect to provide information on the molecular pathology of asthma, and on potential targets such as ITK that may be used to manipulate specific T cell functions involved in allergy and asthma. 2 PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): August, Avery Project Narrative Asthma is an increasingly prevalent disease in the US and other developing countries. T helper 2 cells and cytokines are present in the airways of patients with this disease. The work proposed in this application is highly relevant and significant as we expect to identify the role of Tec kinases in modulating the development of airway inflammation and airways hyperresponsiveness. The data generated from this application will have a significant impact on human health, as we expect to provide information on the molecular pathology of asthma, and on potential targets within T cells that may be used to manipulate their functions involved in asthma. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 10 Continuation Format Page